%0 Journal Article %J Diabetes %D 2017 %T An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. %A Scott, Robert A %A Scott, Laura J %A Mägi, Reedik %A Marullo, Letizia %A Gaulton, Kyle J %A Kaakinen, Marika %A Pervjakova, Natalia %A Pers, Tune H %A Johnson, Andrew D %A Eicher, John D %A Jackson, Anne U %A Ferreira, Teresa %A Lee, Yeji %A Ma, Clement %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Qi, Lu %A Van Zuydam, Natalie R %A Mahajan, Anubha %A Chen, Han %A Almgren, Peter %A Voight, Ben F %A Grallert, Harald %A Müller-Nurasyid, Martina %A Ried, Janina S %A Rayner, Nigel W %A Robertson, Neil %A Karssen, Lennart C %A van Leeuwen, Elisabeth M %A Willems, Sara M %A Fuchsberger, Christian %A Kwan, Phoenix %A Teslovich, Tanya M %A Chanda, Pritam %A Li, Man %A Lu, Yingchang %A Dina, Christian %A Thuillier, Dorothee %A Yengo, Loic %A Jiang, Longda %A Sparso, Thomas %A Kestler, Hans A %A Chheda, Himanshu %A Eisele, Lewin %A Gustafsson, Stefan %A Frånberg, Mattias %A Strawbridge, Rona J %A Benediktsson, Rafn %A Hreidarsson, Astradur B %A Kong, Augustine %A Sigurðsson, Gunnar %A Kerrison, Nicola D %A Luan, Jian'an %A Liang, Liming %A Meitinger, Thomas %A Roden, Michael %A Thorand, Barbara %A Esko, Tõnu %A Mihailov, Evelin %A Fox, Caroline %A Liu, Ching-Ti %A Rybin, Denis %A Isomaa, Bo %A Lyssenko, Valeriya %A Tuomi, Tiinamaija %A Couper, David J %A Pankow, James S %A Grarup, Niels %A Have, Christian T %A Jørgensen, Marit E %A Jørgensen, Torben %A Linneberg, Allan %A Cornelis, Marilyn C %A van Dam, Rob M %A Hunter, David J %A Kraft, Peter %A Sun, Qi %A Edkins, Sarah %A Owen, Katharine R %A Perry, John R B %A Wood, Andrew R %A Zeggini, Eleftheria %A Tajes-Fernandes, Juan %A Abecasis, Gonçalo R %A Bonnycastle, Lori L %A Chines, Peter S %A Stringham, Heather M %A Koistinen, Heikki A %A Kinnunen, Leena %A Sennblad, Bengt %A Mühleisen, Thomas W %A Nöthen, Markus M %A Pechlivanis, Sonali %A Baldassarre, Damiano %A Gertow, Karl %A Humphries, Steve E %A Tremoli, Elena %A Klopp, Norman %A Meyer, Julia %A Steinbach, Gerald %A Wennauer, Roman %A Eriksson, Johan G %A Mӓnnistö, Satu %A Peltonen, Leena %A Tikkanen, Emmi %A Charpentier, Guillaume %A Eury, Elodie %A Lobbens, Stéphane %A Gigante, Bruna %A Leander, Karin %A McLeod, Olga %A Bottinger, Erwin P %A Gottesman, Omri %A Ruderfer, Douglas %A Blüher, Matthias %A Kovacs, Peter %A Tonjes, Anke %A Maruthur, Nisa M %A Scapoli, Chiara %A Erbel, Raimund %A Jöckel, Karl-Heinz %A Moebus, Susanne %A de Faire, Ulf %A Hamsten, Anders %A Stumvoll, Michael %A Deloukas, Panagiotis %A Donnelly, Peter J %A Frayling, Timothy M %A Hattersley, Andrew T %A Ripatti, Samuli %A Salomaa, Veikko %A Pedersen, Nancy L %A Boehm, Bernhard O %A Bergman, Richard N %A Collins, Francis S %A Mohlke, Karen L %A Tuomilehto, Jaakko %A Hansen, Torben %A Pedersen, Oluf %A Barroso, Inês %A Lannfelt, Lars %A Ingelsson, Erik %A Lind, Lars %A Lindgren, Cecilia M %A Cauchi, Stephane %A Froguel, Philippe %A Loos, Ruth J F %A Balkau, Beverley %A Boeing, Heiner %A Franks, Paul W %A Barricarte Gurrea, Aurelio %A Palli, Domenico %A van der Schouw, Yvonne T %A Altshuler, David %A Groop, Leif C %A Langenberg, Claudia %A Wareham, Nicholas J %A Sijbrands, Eric %A van Duijn, Cornelia M %A Florez, Jose C %A Meigs, James B %A Eric Boerwinkle %A Gieger, Christian %A Strauch, Konstantin %A Metspalu, Andres %A Morris, Andrew D %A Palmer, Colin N A %A Hu, Frank B %A Thorsteinsdottir, Unnur %A Stefansson, Kari %A Dupuis, Josée %A Morris, Andrew P %A Boehnke, Michael %A McCarthy, Mark I %A Prokopenko, Inga %K Diabetes Mellitus, Type 2 %K Gene Expression Regulation %K Genetic Variation %K Genome-Wide Association Study %K Humans %K White People %X

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci ( < 5 × 10), including variants near the , , and genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

%B Diabetes %V 66 %P 2888-2902 %8 2017 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/28566273?dopt=Abstract %R 10.2337/db16-1253 %0 Journal Article %J Nat Genet %D 2015 %T Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. %A Gaulton, Kyle J %A Ferreira, Teresa %A Lee, Yeji %A Raimondo, Anne %A Mägi, Reedik %A Reschen, Michael E %A Mahajan, Anubha %A Locke, Adam %A Rayner, N William %A Robertson, Neil %A Scott, Robert A %A Prokopenko, Inga %A Scott, Laura J %A Green, Todd %A Sparso, Thomas %A Thuillier, Dorothee %A Yengo, Loic %A Grallert, Harald %A Wahl, Simone %A Frånberg, Mattias %A Strawbridge, Rona J %A Kestler, Hans %A Chheda, Himanshu %A Eisele, Lewin %A Gustafsson, Stefan %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Qi, Lu %A Karssen, Lennart C %A van Leeuwen, Elisabeth M %A Willems, Sara M %A Li, Man %A Chen, Han %A Fuchsberger, Christian %A Kwan, Phoenix %A Ma, Clement %A Linderman, Michael %A Lu, Yingchang %A Thomsen, Soren K %A Rundle, Jana K %A Beer, Nicola L %A van de Bunt, Martijn %A Chalisey, Anil %A Kang, Hyun Min %A Voight, Benjamin F %A Abecasis, Gonçalo R %A Almgren, Peter %A Baldassarre, Damiano %A Balkau, Beverley %A Benediktsson, Rafn %A Blüher, Matthias %A Boeing, Heiner %A Bonnycastle, Lori L %A Bottinger, Erwin P %A Burtt, Noël P %A Carey, Jason %A Charpentier, Guillaume %A Chines, Peter S %A Cornelis, Marilyn C %A Couper, David J %A Crenshaw, Andrew T %A van Dam, Rob M %A Doney, Alex S F %A Dorkhan, Mozhgan %A Edkins, Sarah %A Eriksson, Johan G %A Esko, Tõnu %A Eury, Elodie %A Fadista, João %A Flannick, Jason %A Fontanillas, Pierre %A Fox, Caroline %A Franks, Paul W %A Gertow, Karl %A Gieger, Christian %A Gigante, Bruna %A Gottesman, Omri %A Grant, George B %A Grarup, Niels %A Groves, Christopher J %A Hassinen, Maija %A Have, Christian T %A Herder, Christian %A Holmen, Oddgeir L %A Hreidarsson, Astradur B %A Humphries, Steve E %A Hunter, David J %A Jackson, Anne U %A Jonsson, Anna %A Jørgensen, Marit E %A Jørgensen, Torben %A Kao, Wen-Hong L %A Kerrison, Nicola D %A Kinnunen, Leena %A Klopp, Norman %A Kong, Augustine %A Kovacs, Peter %A Kraft, Peter %A Kravic, Jasmina %A Langford, Cordelia %A Leander, Karin %A Liang, Liming %A Lichtner, Peter %A Lindgren, Cecilia M %A Lindholm, Eero %A Linneberg, Allan %A Liu, Ching-Ti %A Lobbens, Stéphane %A Luan, Jian'an %A Lyssenko, Valeriya %A Männistö, Satu %A McLeod, Olga %A Meyer, Julia %A Mihailov, Evelin %A Mirza, Ghazala %A Mühleisen, Thomas W %A Müller-Nurasyid, Martina %A Navarro, Carmen %A Nöthen, Markus M %A Oskolkov, Nikolay N %A Owen, Katharine R %A Palli, Domenico %A Pechlivanis, Sonali %A Peltonen, Leena %A Perry, John R B %A Platou, Carl G P %A Roden, Michael %A Ruderfer, Douglas %A Rybin, Denis %A van der Schouw, Yvonne T %A Sennblad, Bengt %A Sigurðsson, Gunnar %A Stančáková, Alena %A Steinbach, Gerald %A Storm, Petter %A Strauch, Konstantin %A Stringham, Heather M %A Sun, Qi %A Thorand, Barbara %A Tikkanen, Emmi %A Tonjes, Anke %A Trakalo, Joseph %A Tremoli, Elena %A Tuomi, Tiinamaija %A Wennauer, Roman %A Wiltshire, Steven %A Wood, Andrew R %A Zeggini, Eleftheria %A Dunham, Ian %A Birney, Ewan %A Pasquali, Lorenzo %A Ferrer, Jorge %A Loos, Ruth J F %A Dupuis, Josée %A Florez, Jose C %A Eric Boerwinkle %A Pankow, James S %A van Duijn, Cornelia %A Sijbrands, Eric %A Meigs, James B %A Hu, Frank B %A Thorsteinsdottir, Unnur %A Stefansson, Kari %A Lakka, Timo A %A Rauramaa, Rainer %A Stumvoll, Michael %A Pedersen, Nancy L %A Lind, Lars %A Keinanen-Kiukaanniemi, Sirkka M %A Korpi-Hyövälti, Eeva %A Saaristo, Timo E %A Saltevo, Juha %A Kuusisto, Johanna %A Laakso, Markku %A Metspalu, Andres %A Erbel, Raimund %A Jöcke, Karl-Heinz %A Moebus, Susanne %A Ripatti, Samuli %A Salomaa, Veikko %A Ingelsson, Erik %A Boehm, Bernhard O %A Bergman, Richard N %A Collins, Francis S %A Mohlke, Karen L %A Koistinen, Heikki %A Tuomilehto, Jaakko %A Hveem, Kristian %A Njølstad, Inger %A Deloukas, Panagiotis %A Donnelly, Peter J %A Frayling, Timothy M %A Hattersley, Andrew T %A de Faire, Ulf %A Hamsten, Anders %A Illig, Thomas %A Peters, Annette %A Cauchi, Stephane %A Sladek, Rob %A Froguel, Philippe %A Hansen, Torben %A Pedersen, Oluf %A Morris, Andrew D %A Palmer, Collin N A %A Kathiresan, Sekar %A Melander, Olle %A Nilsson, Peter M %A Groop, Leif C %A Barroso, Inês %A Langenberg, Claudia %A Wareham, Nicholas J %A O'Callaghan, Christopher A %A Gloyn, Anna L %A Altshuler, David %A Boehnke, Michael %A Teslovich, Tanya M %A McCarthy, Mark I %A Morris, Andrew P %K Binding Sites %K Case-Control Studies %K Chromatin Immunoprecipitation %K Chromosome Mapping %K Diabetes Mellitus, Type 2 %K Gene Expression Regulation %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomics %K Hepatocyte Nuclear Factor 3-beta %K Humans %K Islets of Langerhans %K Liver %K Molecular Sequence Annotation %K Polymorphism, Single Nucleotide %K Receptor, Melatonin, MT2 %X

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

%B Nat Genet %V 47 %P 1415-25 %8 2015 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/26551672?dopt=Abstract %R 10.1038/ng.3437